Pre-clinical fluoropropylthio-TZTP studies in rodents and monkeys support our hypothesis that F-18 fiuoropropylthio-TZTP, a derivative of a muscarinic agonist developed by Novo-Nordisk, is an M2 selective ligand. Kinetic analysis of fluoropropylthio-TZTP shows that the volume of distribution can be measured in vivo using external PET imaging and that this tracer may be useful for the measurement of M2 cholinergic receptor changes in vivo. Infusion of physostigmine to increase the concentration of acetylcholine in the synapse produced a 24% reduction in cortical volumes of distribution, consistent with increased acetylcholine concentrations. We have developed a series of 11C and 18F labeled antagonists for the 5HT1a and 5HT2a receptor. The compounds tested have high specificity for the receptor class and high receptor specificity for the receptor subtype. Distribution studies in vivo are consistent with 5HT receptor binding. We have synthesized five derivatives of WAY 100635 [(N-(2-( l -(4-(2- methoxypheny1)- 1 -piperazinyl) ethyl)-N(2 pyridyl) cyclohexanecarboxamide] using various acids to replace the cyclohexylcarboxylic acid. The four acids are 4-fiuorobenzoic acid (FBA), 3-methyl,4-fiuorobenzoic acid (MeFBA), 4-fluoromethylbenzoic acid (FMeBA), 3-nitro,4-fiuoromethylbenzoic acid (NFMeBA) and 4-cis fiuorocyclohexylcarboxylic acid (FCA). The major metabolite in blood in all studies was the corresponding carboxylic acid. The [18F] FCWAY appears to have the same pharmacokinetic properties as WAY with the advantage of the longer half life of 18F and the possibility to reach steady-state, which could facilitate measurements in humans. Studies are being carried out in monkeys to confirm this. We have studied the ability of lysine to decrease the residence time of [18F] radio-labeled anti-TAC dsFv (a fragment with high affinity for the interleukin-2 receptor alpha chain) in the rat and the baboon kidney. The most effective renal blocking of dsFv occurs with intravenous co-injection of lysine or alternately intraperitoneal injection 2 min. prior to dsFv. We have labeled both methionine and lysine contained in anti-TAC dsFv with a Ga chelate and followed the catabolism of the tracer in the kidney. The methionine conjugate appears to be cleared more rapidly from the kidney than the lysine conjugate and appears more rapidly in the urine. Therefore, either blockade of the kidney uptake using lysine or decreased kidney residence time using amino-acid-specific labeling may decrease the amount of low molecular weight protein in the kidney.